Melkersson-Rosenthal Syndrome: a case report and overview
of the literature
Pinna M.¹, Orrù G. ¹, Denotti G. ¹, Murgia M. S. ¹, Casu C.
¹,²
Department of Surgical Sciences, Oral Biotechnology Laboratory,
Cagliari State University, Cagliari, Italy;mme.pinna@gmail.com;orru@unica.it ;gloriadenotti@gmail.com;martina.murgia.s@gmail.com; ginzia.85@hotmail.it;
International PhD in Innovation Sciences and Technologies, Cagliari
State University, Cagliari, Italy;ginzia.85@hotmail.it;
Corresponding authors: Casu Cinzia,ginzia.85@hotmail.it; Orrù
Germano, orru@unica.it; Pinna Mara,mme.pinna@gmail.com
Abstract
Melkersson – Rosenthal Syndrome (MRS) is a rare disorder with a still
unknown etiology. It is defined by three main symptoms, which are
orofacial granulomatosis (OFG), facial palsy and fissured tongue. It
generally presents in young people, during the second or third decade,
and its incidence in the entire population is about 1%. We focus our
attention on a 69 year – old man who came to us with an important
swelling of the upper lip. His anamnesis revealed that he suffered from
a facial palsy four times in his life and at the physical examination we
attested the presence of scrotal tongue. We suspected a misdiagnosed MRS
and we searched the web in order to give him a diagnosis and a therapy.
We found that OFG is the most common symptom of MRS and that it can show
as a non complete form, where the three main symptoms cannot occur
simultaneously. We also prescribed a therapy based on the use of topic
steroids and antiviral, according to literature. After the positive
response to the therapy and according to data found in the most recent
literature, we can assume that our patient suffers from a misdiagnosed
MRS for about forty years.
Keywords : Melkersson Rosenthal Syndrome; orofacial
granulomatosis; lip oedema; Miescher cheilitis; relapsing facial palsy;
Melkersson Rosenthal Syndrome and Covid 19.
Introduction
Melkersson – Rosenthal Syndrome is a rare neuro-muco-cutaneous disorder
associated with three main symptoms, which are recurrent orofacial
swelling, relapsing facial palsy and fissured tongue. Its etiology is
still unknown; it is suggested that viral infections, allergic factors
and hereditary genes (1) can be associated with the spread of the
disease. Many authors suggest that it could be an autoimmune disorder,
due to the high positivity to the anti - SS – A, anti – RNP
autoantibody (2) and elevated serum levels of the angiotensin converting
enzyme (3). Orofacial swelling, also defined as Orofacial Granulomatosis
(OFG), is a condition that can interest the entire face of the patient,
and it is characterized by oedema of the soft tissues, histologically
defined by the” presence of non-caseating epithelioid cell granulomas
undistinguishable to sarcoidosis and Crohn disease” (4). If the
swelling pertains to the lips – in the most of the cases only the upper
– we can refer to OFG as Granulomatous Cheilitis (GC), and it
represents the most common symptom of MRS. Facial palsy is often
clinically confused with Bell’s palsy, even if this kind of paralysis
can be bilateral and more severe than Bell’s one (5). Another symptom
that occurs infrequently is facial palsy. Fissured tongue or “lingua
plicata” is an idiopathic condition that can be congenital and benign,
but, if associated with at least one of these two symptoms – and in
particular with GC - can be characteristic of MRS. Concerning
epidemiology, MRS has no racial and/or geographical preference, whereas
prefers women (4), like autoimmune diseases, supporting this origin as
its pathogenesis. Here we present a case of a 69 year –old man with
misdiagnosed MRS for about 40 years.
1.1 Case Presentation
A 69 year-old male patient went to our observation for a condition of
recurrent swelling on the upper lip. Anamnesis was positive for type 2
diabetes. He reported 4 cases of facial paresis in his life, about 1
each 10 years. On objective examination it was possible to see the
presence of fissured tongue (fig. 1,2) and an erythematous, not painful
and swelling upper lip present from about 3-4 years (fig. 4). The
patient reported us that from some years, every 4-6 months he had very
similar episodes at the lip level and that they were treated with
systemic beta-methasone (2 mg for 3 days and 1 mg for 2 days) by his
family doctor, without a precise diagnosis being made.
We suspected a case of Melkersson Rosenthal Syndrome, given the
association with the 3 condition, and we suggested the patients follow
up visits. We prescribed topical and systemic corticosteroids in case of
other episodes of facial paresis and/or swelling of the lip. We
suggested also the association with antiviral therapy with Acyclovir 200
mg for 5 times a day for 7 days in case of paresis presentation.
An analysis of the literature has been made in order to establish if our
patient suffers from Melkersson – Rosenthal Syndrome.
Discussion
Main symptoms and their presentation
Melkersson - Rosenthal Syndrome is a rare disorder characterized by a
triad of symptoms, which classically are orofacial granulomatosis,
facial palsy and lingua plicata. Historically, the first case of this
disease was observed by Melkersson in 1928 in a woman presenting lip
oedema and intermittent peripheral facial palsy; subsequently, Rosenthal
in 1931 noted the presence of fissured tongue in these kind of patients,
and added it to the list of the symptoms, defining the Melkersson –
Rosenthal Syndrome (MRS) (4,6,7). When all these symptoms occur
simultaneously, it is very easy to make diagnosis. Unfortunately, MRS
can show as a mono- or oligosymptomatic disorder. According to Mansour
et al. (13) and Ozgursoy et al. (12), only in 8 – 18 percentage of
cases the complete triad of symptoms occurs, percentage that increases
up to 25 according to other authors (8,9). The most frequent symptom is
orofacial granulomatosis (OFG), which is reported in 80 – 100% of MRS
diagnosis (6) . OFG is defined as an uncommon and chronic inflammatory
condition of unknown etiology (7) that affects intra and extraoral
mucosal tissues of the head and neck. The site it hits the most is the
upper lip, then it can affect the lower lip, the cheek, the buccal
mucosa, the eyelid and can even have a wider involvement of the whole
face of the patient (6,9). In the event of only interest of the lips, it
can be referred as Cheilitis Granulomatosa (CG). It is well supported
from literature that the oedema characterizing OFG and CG is typically
acute, painless and non-pitting and histopathologically marked out by
the presence of non-caseating epithelioid cell granulomas and
lymphoedema (4, 5, 7, 8, 10, 11). There is disagreement in literature
about the definition of OFG and CG: CG is a chronic swelling of the lips
– one or both simultaneously – due to granulomatous inflammation which
was described by Miescher for the first time in 1945 – and so called
Miescher’s cheilitis, too (4, 7). OFG is a term used for the first time
in 1985 by Wiesenfield that encompasses both MRS and CG (4, 7).
Histopathologically, these two conditions are very similar, and they can
present or not non – caseating epithelioid cell granulomas
indistinguishable from Crohn’s disease or sarcoidosis (4). That’s the
reason why histology cannot be considered the gold standard for a
diagnosis of CG or OFG. Indeed, it is well understood that both OFG and
CG could represent a monosymptomatic form of MRS (4), where CG
definitely is the most frequent form of presentation. Patients with OFG
or CG should be in any way investigated for Crohn’s Disease, too, since
the association with this disorder is well established in literature
(11), and in order to rule out one disease or other. Thus, some authors
believe that CG or, more in general OFG, is very rare if in association
with Crohn’s disease – about 0.05% - (7), and they assert that CG can
be seen as a subtype of MRS. MRS can show as a oligosymptomatic form
too, and in this case, facial palsy is the second more common symptom.
According to data found in literature, facial nerve paralysis occurs in
30 -80 % of patients (6, 9, 12). Clinically, it can be confused with
Bell’s palsy, and this takes to a misdiagnosis of MRS. Facial nerve
palsy presents more often as a unilateral and relapsing, partial or
complete paralysis of the seventh nerve. Episodes of paralysis usually
last longer than Bell’s ones, and have worse prognosis, since this kind
of palsy can lead to fibrosis of the neural tissue. (9). Moreover, in
some cases the lesion can affect other cranial nerves, defining other
kind of neuropathies such as tinnitus or hearing loss (with the
involvement of the VIII cranial nerve), migraine (with the involvement
of V cranial nerve) and dysgeusia (with the involvement of IX cranial
nerve) (5, 9). The last symptom associated with MRS is lingua plicata,
or scrotal or fissured tongue. It is considered as a developmental
malformation with an extimated incidence of 0.5 – 5% in the general
population (9, 12). It can also be idiopathic and not involved in MRS,
but, according to data from literature, 30 – 80% of patients with
suspected MRS shows a fissured tongue (9, 12). In the presence of two of
these three symptoms, it is quite clear that the patient suffers from
MRS. MRS can be defined as a clinical syndrome (9, 13) which means that
it does not require histology for establishing a diagnosis. As already
said before, there are no typical histological features that can assure
a diagnosis of MRS, and at the same time, there are no specific
biomarkers or imaging tests that can confirm a certain diagnosis. It can
be assumed that MRS is a clinical and of exclusion diagnosis (9).
Epidemiology and Etiology
MRS is a rare disease that affects 0.08% of the worldwide population
(4, 5, 8), but it is still considered as a mis - and underdiagnosed
disease because of its unclear presentation. As mentioned before, when
in presence of one symptoms only – or sometimes two - it can be very
difficult to make diagnosis. That’s the reason why there is agreement in
literature that the incidence could be higher (9). It is also reported
that it is even rarer in childhood (9). Since the disease could present
as a mono or oligosymptomatic form, a delay of four years in average in
the diagnosis of MRS can be found (5). Its etiology is still uncertain,
and genetics, immunological disorders, infective origins and food or
atopic reactions are taken in count. About this last topic, there is a
little evidence that in some cases MRS – especially the OFG symptom -
can be associated with intolerance to cinnamon and benzoates (4, 7).
These data can be regarded, but they still need further investigations.
Another hypothesis that longs to be more analyzed is that MRS can be
seen as an early manifestation of Mixed Connective Tissue Diseases
(MCTD), such as Systemic Lupus Erythematosus or Sclerodermia (2).
According to this theory, MRS can be seen as the primary manifestation
of a wider disease, with a bigger involvement of the neurological
functions and of the whole body (4). This theory is also in need of a
major in-depth analysis.
It seems quite clear instead that MRS undergoes to a male –to –male
vertical transmission (14). Genetics play a fundamental role in the
expression of the disease, as it is demonstrated by Xu et al. (15) in
their study of a Han Chinese family, where the authors found that a
mutation in a gene of a fatty acid transport protein (FATP-1), a protein
responsible for the fatty acids uptake and metabolism and robustly
expressed in skin, happened. This suggestion is also confirmed by
another study conducted in a Tunisian family by Mansour et al. (13),
where a paternal and a genetic inheritance as an autosomal dominant
disease is proposed, according to Lygidakis et al. (14) and Xu et al.
(15). However, there is no complete agreement in this genetic theory:
Pei et al. (10) suggest that genetic heterogeneity or genetic modifiers
such as female hormones (in agreement with Elias et al. (5), too) can be
considered as the causal factors in the etiology of MRS, since their
cluster of patients with certain diagnosis of MRS did not present the
FATP-1 mutation (10). This means that there is still the need of more
studies of the genetic causes.
Talking about incidence, according to Wehl et al. (4) and Zewde (6), it
more often presents during the second or third decade, and it prefers
women rather than men. Since young women are preferred, this leans
toward an autoimmune etiology, where sex hormones together with
predisposing factors (9) can cause the disease. An infective origin of
the disorder is also under debate: many authors (6, 8, 9, 12) believe
that a viral or a bacterial infection can behave as a trigger to the
manifestation of the disease, which sparkles the immune system giving
rise to an abnormal response against non –self antigens (9). In the
analyzed literature, patients were screened in order to rule out other
concomitant infections, such as EBV, ZVZ, CMV, HSV or M.
tubercolosis, B. burgdoriferi. In the light of these events, there is
an interesting and brand new association with the infection of the SARS
– Cov – 2 virus and MRS. Covid- 19 pandemic is nowadays the most
important sanitary issue every Nation is fighting. Beyond the typical
pulmonary presentation of the disease, it is well established that it
can affect the entire body and so the mouth, too. It is strongly
supported that the virus enters the human cells through the Angiotensin
Converting Enzyme 2 (ACE-2) receptors, which are extremely represented
in the lungs, in the salivary glands and in the surface of the tongue
(16, 17). After the colonization, in predisposed patients it leads to
the cytokine storms and the pulmonary disease characterized by a glass
appearance of the chest in X-rays and TC scan (16). Since it affects
primary the tongue, it is quite clear that it can cause oral lesions,
too. Hence, the typical lesions caused by Covid -19 infection in the
oropharyngeal tract are dysgeusia and ageusia, ulcerations and petechiae
of the whole oral cavity and geographical tongue (17). The association
between MRS and Covid -19 infection is reported in few cases in
literature until now. Taslidere et al. (8) reported a case of a 51 year
old woman with diagnosed MRS who came to their attention with swollen
lip and SARS – Cov – 2 symptoms. A series of laboratory test revealed
that she suffered from Covid -19 infection and that the swollen lip,
histopathologically defined as presenting areas of inflammation
involving granulomas, Langhans giant cells and mast cells, could be
referred as an exacerbation of MRS. Mast cells are believed to be the
link between the manifestation of Covid – 19 symptoms and MRS, because
of their role in the occurrence of the immune response. Mast cells
activate the inflammatory response giving rise to the cytokine storm
which verifies during the manifestation of the disease (8). RCP is
another protein being part of the cytokines that is believed to play a
role in the manifestation of MRS related to Covid – 19 infection. High
RCP levels are detected in Covid – 19 patients and in MRS patients, too
(16, 17). Nevertheless, this hypothesis of association with infections
– and in particular with SARS – Cov -2 – needs further
investigations.
Therapy
According to literature, a standardized therapy for symptomatic MRS does
not exist. Most authors suggest corticosteroids in order to decrease
facial swelling and to re-establish the compliance of the seventh nerve.
Use of topic or systemic corticosteroids depends on the severity of the
disease. A long – term therapy (about 3 -6 weeks) with prednisone or
triamcinolone is usually prescribed (4, 9). Interestingly, there is
quite agreement in literature that MRS’ facial palsy does not respond to
antihistamines drugs (5, 9, 12), and that this factor can contribute to
rule out Bell’s palsy in a differential diagnosis. Thus, Zewde (6)
reports that antihistamine drugs can be used as a therapy in MRS, too.
This is controversial and needs further investigations. When triggered
by infections, as in the case of MRS related to Covid – 19, giving a
therapy for the primary infection can reduce and eliminate all the
symptoms of MRS, as demonstrated by Taslidere et al. (8).
Conclusions
We tried to analyze our patient’s symptoms as three distinct units,
considering he could suffer from Bell’s palsy and CG. Lingua plicata, as
already said before, can be considered an idiopathic feature. We
referred at the most recent literature in order to provide a correct
diagnosis for our patient’s symptoms. In the light of the events, we can
assume that our patient suffers from a MRS which has been misdiagnosed
for about 40 years, because of its oligosymptomatic manifestation and
its rare incidence in the population. Even the therapy given for the lip
swelling is correct, according to literature. Interestingly, our patient
responded positively to the topic corticosteroids, and in only five days
he referred a complete regression of the swelling of the upper lip (fig.
4,5).